PROJECT SUMMARY Identification of undiagnosed hepatitis C virus (HCV) infection and effective linkage-to-care is a critical public health priority. In the United States, over 3 million individuals are chronically infected with HCV, of which the majority (>50%) remain undiagnosed. The Centers for Disease Control and Prevention and U.S. Preventive Services Task Force recommend screening all individuals born from 1945 through 1965 (i.e., ?birth cohort?) and non-birth cohort individuals with known risks for HCV infection (e.g., people who inject drugs) to increase diagnoses, treatment, and cure, while reversing the increasing incidence, morbidity, mortality, and healthcare costs associated with HCV infection. Emergency departments (EDs) have been a major focus of infectious diseases screening, including human immunodeficiency virus (HIV) infection and, more recently, HCV infection. This focus is prompted by the fact that over 135 million ED visits occur annually in the United States, EDs serve large proportions of underserved and at-risk patients, and EDs are common sites of missed diagnostic opportunities. Our research team has pioneered investigations in ED-based HIV and HCV screening since 2004 with the overarching goal of determining the most effective and efficient methods of screening among high-risk populations in EDs. To build on our work, we propose the following specific aims: (1) to compare the effectiveness of non-risk-based (nontargeted) and risk-based (targeted) HCV screening when integrated into urban EDs; (2) to compare the effectiveness of linkage navigation plus clinician referral versus clinician referral alone for HCV-infected patients identified in EDs; and (3) to estimate programmatic costs and project long-term outcomes and cost effectiveness of ED-based HCV screening and linkage to care. In doing so, we will perform the following studies: (a) a multi-center prospective pragmatic randomized effectiveness trial to test whether nontargeted HCV screening is significantly associated with newly-diagnosed HCV infection when compared to targeted HCV screening; (b) a distinct single-center prospective pragmatic randomized effectiveness trial to test whether linkage navigation significantly increases the proportion of newly diagnosed patients who complete primary care visits for HCV infection and progress through the HCV Care Continuum when compared to standard clinician referral; (c) a nested prospective cohort study using time-motion methods and actual trial expenses to estimate direct costs per newly-diagnosed HCV infection for each screening method; and (d) an analysis with results from both clinical trials to parameterize a Monte Carlo transition-state simulation model of HCV screening, treatment, and disease progression to test whether nontargeted HCV screening coupled with linkage navigation will yield the best outcomes and be cost effective. This project will be the largest and most comprehensive evaluation of HCV screening in EDs to date, the results will substantially improve our understanding of how to provide effective rapid HCV screening and linkage-to-care of ED patients, and will have a sustained and powerful influence on the HCV epidemic in the United States.